scholarly journals High-Fat Overfeeding Impairs Peripheral Glucose Metabolism and Muscle Microvascular eNOS Ser1177 Phosphorylation

2019 ◽  
Vol 105 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Siôn A Parry ◽  
Mark C Turner ◽  
Rachel M Woods ◽  
Lewis J James ◽  
Richard A Ferguson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glycemic Control ◽  
Insulin Signaling ◽  
Dietary Fat ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Whole Body ◽  
High Fat ◽  
Before And After ◽  
Protein Ingestion

Abstract Context The mechanisms responsible for dietary fat-induced insulin resistance of skeletal muscle and its microvasculature are only partially understood. Objective To determine the impact of high-fat overfeeding on postprandial glucose fluxes, muscle insulin signaling, and muscle microvascular endothelial nitric oxide synthase (eNOS) content and activation. Design Fifteen non-obese volunteers consumed a high-fat (64%) high-energy (+47%) diet for 7 days. Experiments were performed before and after the diet. Stable isotope tracers were used to determine glucose fluxes in response to carbohydrate plus protein ingestion. Muscle insulin signaling was determined as well as the content and activation state of muscle microvascular eNOS. Results High-fat overfeeding impaired postprandial glycemic control as demonstrated by higher concentrations of glucose (+11%; P = 0.004) and insulin (+19%; P = 0.035). Carbohydrate plus protein ingestion suppressed endogenous glucose production to a similar extent before and after the diet. Conversely, high-fat overfeeding reduced whole-body glucose clearance (–16%; P = 0.021) and peripheral insulin sensitivity (–26%; P = 0.006). This occurred despite only minor alterations in skeletal muscle insulin signaling. High-fat overfeeding reduced eNOS content in terminal arterioles (P = 0.017) and abolished the increase in eNOS Ser1177 phosphorylation that was seen after carbohydrate plus protein ingestion. Conclusion High-fat overfeeding impaired whole-body glycemic control due to reduced glucose clearance, not elevated endogenous glucose production. The finding that high-fat overfeeding abolished insulin-mediated eNOS Ser1177 phosphorylation in the terminal arterioles suggests that impairments in the vasodilatory capacity of the skeletal muscle microvasculature may contribute to early dietary fat-induced impairments in glycemic control.

Decreased PDH activation and glycogenolysis during exercise following fat adaptation with carbohydrate restoration

2006 ◽  
Vol 290 (2) ◽  
pp. E380-E388 ◽  
Author(s):  
Trent Stellingwerff ◽  
Lawrence L. Spriet ◽  
Matthew J. Watt ◽  
Nicholas E. Kimber ◽  
Mark Hargreaves ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Total Energy ◽  
Random Order ◽  
Fat Oxidation ◽  
Whole Body ◽  
Peak Power Output ◽  
High Fat ◽  
Regulatory Enzymes ◽  
Before And After ◽  
Experimental Trials

Five days of a high-fat diet while training, followed by 1 day of carbohydrate (CHO) restoration, increases rates of whole body fat oxidation and decreases CHO oxidation during aerobic cycling. The mechanisms responsible for these shifts in fuel oxidation are unknown but involve up- and downregulation of key regulatory enzymes in the pathways of skeletal muscle fat and CHO metabolism, respectively. This study measured muscle PDH and HSL activities before and after 20 min of cycling at 70% V̇o2 peak and 1 min of sprinting at 150% peak power output (PPO). Estimations of muscle glycogenolysis were made during the initial minute of exercise at 70% V̇o2 peak and during the 1-min sprint. Seven male cyclists undertook this exercise protocol on two occasions. For 5 days, subjects consumed in random order either a high-CHO (HCHO) diet (10.3 g·kg−1·day−1 CHO, or ∼70% of total energy intake) or an isoenergetic high-fat (FAT-adapt) diet (4.6 g·kg−1·day−1 FAT, or 67% of total energy) while undertaking supervised aerobic endurance training. On day 6 for both treatments, subjects ingested an HCHO diet and rested before their experimental trials on day 7. This CHO restoration resulted in similar resting glycogen contents (FAT-adapt 873 ± 121 vs. HCHO 868 ± 120 μmol glucosyl units/g dry wt). However, the respiratory exchange ratio was lower during cycling at 70% V̇o2 peak in the FAT-adapt trial, which resulted in an ∼45% increase and an ∼30% decrease in fat and CHO oxidation, respectively. PDH activity was lower at rest and throughout exercise at 70% V̇o2 peak (1.69 ± 0.25 vs. 2.39 ± 0.19 mmol·kg wet wt−1·min−1) and the 1-min sprint in the FAT-adapt vs. the HCHO trial. Estimates of glycogenolysis during the 1st min of exercise at 70% V̇o2 peak and the 1-min sprint were also lower after FAT-adapt (9.1 ± 1.1 vs. 13.4 ± 2.1 and 37.3 ± 5.1 vs. 50.5 ± 2.7 glucosyl units·kg dry wt−1·min−1). HSL activity was ∼20% higher ( P = 0.12) during exercise at 70% V̇o2 peak after FAT-adapt. Results indicate that previously reported decreases in whole body CHO oxidation and increases in fat oxidation after the FAT-adapt protocol are a function of metabolic changes within skeletal muscle. The metabolic signals responsible for the shift in muscle substrate use during cycling at 70% V̇o2 peak remain unclear, but lower accumulation of free ADP and AMP after the FAT-adapt trial may be responsible for the decreased glycogenolysis and PDH activation during sprinting.

scholarly journals High-Fat Diet-Mediated Lipotoxicity and Insulin Resistance Is Related to Impaired Lipase Expression in Mouse Skeletal Muscle

Endocrinology ◽  
2013 ◽  
Vol 154 (4) ◽  
pp. 1444-1453 ◽  
Author(s):  
Pierre-Marie Badin ◽  
Isabelle K. Vila ◽  
Katie Louche ◽  
Aline Mairal ◽  
Marie-Adeline Marques ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase ◽  
Protein Content ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Whole Body ◽  
Wild Type ◽  
High Fat ◽  
Lipase Expression

Abstract Elevated expression/activity of adipose triglyceride lipase (ATGL) and/or reduced activity of hormone-sensitive lipase (HSL) in skeletal muscle are causally linked to insulin resistance in vitro. We investigated here the effect of high-fat feeding on skeletal muscle lipolytic proteins, lipotoxicity, and insulin signaling in vivo. Five-week-old C3H mice were fed normal chow diet (NCD) or 45% kcal high-fat diet (HFD) for 4 weeks. Wild-type and HSL knockout mice fed NCD were also studied. Whole-body and muscle insulin sensitivity, as well as lipolytic protein expression, lipid levels, and insulin signaling in skeletal muscle, were measured. HFD induced whole-body insulin resistance and glucose intolerance and reduced skeletal muscle glucose uptake compared with NCD. HFD increased skeletal muscle total diacylglycerol (DAG) content, protein kinase Cθ and protein kinase Cϵ membrane translocation, and impaired insulin signaling as reflected by a robust increase of basal Ser1101 insulin receptor substrate 1 phosphorylation (2.8-fold, P < .05) and a decrease of insulin-stimulated v-Akt murine thymoma viral oncogene homolog Ser473 (−37%, P < .05) and AS160 Thr642 (−47%, P <.01) phosphorylation. We next showed that HFD strongly reduced HSL phosphorylation at Ser660. HFD significantly up-regulated the muscle protein content of the ATGL coactivator comparative gene identification 58 and triacylglycerol hydrolase activity, despite a lower ATGL protein content. We further show a defective skeletal muscle insulin signaling and DAG accumulation in HSL knockout compared with wild-type mice. Together, these data suggest a pathophysiological link between altered skeletal muscle lipase expression and DAG-mediated insulin resistance in mice.

Site of Insulin Resistance after Surgery: The Contribution of Hypocaloric Nutrition and Bed Rest

1997 ◽  
Vol 93 (2) ◽  
pp. 137-146 ◽  
Author(s):  
Jonas Nygren ◽  
Anders Thorell ◽  
Suad Efendic ◽  
K. Sree Nair ◽  
Olle Ljungqvist
Keyword(s):  
Insulin Resistance ◽  
Glucose Oxidation ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Bed Rest ◽  
Endogenous Glucose Production ◽  
Whole Body ◽  
Glucose Disposal ◽  
Before And After ◽  
Endogenous Glucose

1. Insulin resistance after surgery has been shown to be related to several important derangements in protein and fat metabolism. However, mechanisms of impaired glucose tolerance after surgery remain ill-defined. 2. Insulin sensitivity and glucose kinetics (6,62H2-glucose) were studied in seven patients before and after elective surgery (surgery group), by two step-hyperinsulinaemic (0.3 and 0.8 munits kg−1 min−1), normoglycaemic (4.5 mmol/l) clamps. Six healthy subjects were studied, using the same protocol, before and after a similar period of bed rest and hypocaloric nutrition (fast/bed rest group) to delineate the effects of surgery per se. 3. Basal endogenous glucose production and whole-body glucose disposal was higher after surgery (P < 0.001), whereas no change was found after fast/bed rest. During glucose clamps, the glucose infusion rates required to maintain normoglycaemia and whole-body glucose disposal decreased (P < 0.001) after surgery, while endogenous glucose production increased (P < 0.001). In the control subjects, levels of endogenous glucose production remained unchanged after fast/bed rest. In contrast, glucose infusion rates and whole-body glucose disposal during glucose clamps also decreased after fast/bed rest (P < 0.01). However, the relative decrease in both these parameters was greater after surgery compared with after fast/bed rest (P < 0.01). 4. After surgery, energy expenditure and fat oxidation increased (P < 0.001), whereas glucose oxidation decreased (P < 0.05). No significant change was found in glucose utilization postoperatively. After fast/bed rest, no change was found in energy expenditure. However, fat oxidation increased (P < 0.01), whereas glucose oxidation and glucose utilization decreased (P < 0.05). 5. In conclusion, impaired glucose tolerance develops after surgery as a result of decreased insulin-stimulated whole-body glucose disposal as well as increased endogenous glucose release. Despite the increase in endogenous glucose production, the reduction in endogenous glucose production with each elevation of insulin was unaffected by surgery. Perioperative bed rest and/or hypocaloric nutrition contribute to the decrease in insulin-stimulated whole-body glucose disposal in the postoperative state, whereas these factors have no effects on endogenous glucose production.

scholarly journals Paternal high-fat diet enhances offspring whole-body insulin sensitivity and skeletal muscle insulin signaling early in life

2018 ◽  
Vol 6 (5) ◽  
pp. e13583 ◽  
Author(s):  
Leslie A. Consitt ◽  
Gunjan Saxena ◽  
Yuriy Slyvka ◽  
Brian C. Clark ◽  
Max Friedlander ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Whole Body ◽  
High Fat

scholarly journals Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice

2020 ◽  
Vol 117 (51) ◽  
pp. 32584-32593
Author(s):  
Xiruo Li ◽  
Dongyan Zhang ◽  
Daniel F. Vatner ◽  
Leigh Goedeke ◽  
Sandro M. Hirabara ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Serine Phosphorylation ◽  
Whole Body ◽  
Acid Oxidation ◽  
Ceramide Content ◽  
Stimulation Of

Adiponectin has emerged as a potential therapy for type 2 diabetes mellitus, but the molecular mechanism by which adiponectin reverses insulin resistance remains unclear. Two weeks of globular adiponectin (gAcrp30) treatment reduced fasting plasma glucose, triglyceride (TAG), and insulin concentrations and reversed whole-body insulin resistance, which could be attributed to both improved insulin-mediated suppression of endogenous glucose production and increased insulin-stimulated glucose uptake in muscle and adipose tissues. These improvements in liver and muscle sensitivity were associated with ∼50% reductions in liver and muscle TAG and plasma membrane (PM)-associated diacylglycerol (DAG) content and occurred independent of reductions in total ceramide content. Reductions of PM DAG content in liver and skeletal muscle were associated with reduced PKCε translocation in liver and reduced PKCθ and PKCε translocation in skeletal muscle resulting in increased insulin-stimulated insulin receptor tyrosine1162 phosphorylation, IRS-1/IRS-2–associated PI3-kinase activity, and Akt-serine phosphorylation. Both gAcrp30 and full-length adiponectin (Acrp30) treatment increased eNOS/AMPK activation in muscle and muscle fatty acid oxidation. gAcrp30 and Acrp30 infusions also increased TAG uptake in epididymal white adipose tissue (eWAT), which could be attributed to increased lipoprotein lipase (LPL) activity. These data suggest that adiponectin and adiponectin-related molecules reverse lipid-induced liver and muscle insulin resistance by reducing ectopic lipid storage in these organs, resulting in decreased plasma membranesn-1,2-DAG–induced nPKC activity and increased insulin signaling. Adiponectin mediates these effects by both promoting the storage of TAG in eWAT likely through stimulation of LPL as well as by stimulation of AMPK in muscle resulting in increased muscle fat oxidation.

Increased glucose production in mice overexpressing human fructose-1,6-bisphosphatase in the liver

2008 ◽  
Vol 295 (5) ◽  
pp. E1132-E1141 ◽  
Author(s):  
Sherley Visinoni ◽  
Barbara C. Fam ◽  
Amy Blair ◽  
Christian Rantzau ◽  
Benjamin J. Lamont ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Transgenic Mice ◽  
Glucose Homeostasis ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Whole Body ◽  
High Fat ◽  
Transgenic Model ◽  
Fructose 1,6 Bisphosphatase

Increased endogenous glucose production (EGP) predominantly from the liver is a characteristic feature of type 2 diabetes, which positively correlates with fasting hyperglycemia. Gluconeogenesis is the biochemical pathway shown to significantly contribute to increased EGP in diabetes. Fructose-1,6-bisphosphatase (FBPase) is a regulated enzyme in gluconeogenesis that is increased in animal models of obesity and insulin resistance. However, whether a specific increase in liver FBPase can result in increased EGP has not been shown. The objective of this study was to determine the role of upregulated liver FBPase in glucose homeostasis. To achieve this goal, we generated human liver FBPase transgenic mice under the control of the transthyretin promoter, using insulator sequences to flank the transgene and protect it from site-of-integration effects. This resulted in a liver-specific model, as transgene expression was not detected in other tissues. Mice were studied under the following conditions: 1) at two ages (24 wk and 1 yr old), 2) after a 60% high-fat diet, and 3) when bred to homozygosity. Hemizygous transgenic mice had an approximately threefold increase in total liver FBPase mRNA with concomitant increases in FBPase protein and enzyme activity levels. After high-fat feeding, hemizygous transgenics were glucose intolerant compared with negative littermates ( P < 0.02). Furthermore, when bred to homozygosity, chow-fed transgenic mice showed a 5.5-fold increase in liver FBPase levels and were glucose intolerant compared with negative littermates, with a significantly higher rate of EGP ( P < 0.006). This is the first study to show that FBPase regulates EGP and whole body glucose homeostasis in a liver-specific transgenic model. Our homozygous transgenic model may be useful for testing human FBPase inhibitor compounds with the potential to treat patients with type 2 diabetes.

Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin

2001 ◽  
Vol 281 (2) ◽  
pp. E275-E282 ◽  
Author(s):  
Shaoming Song ◽  
Sofianos Andrikopoulos ◽  
Christine Filippis ◽  
Anne W. Thorburn ◽  
David Khan ◽  
...  
Keyword(s):  
Dietary Fat ◽  
High Fat Diet ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Protein Levels ◽  
Fructose 1,6 Bisphosphatase ◽  
Endogenous Glucose ◽  
Fat Feeding

High-fat feeding has been shown to cause hepatic insulin resistance. The aims of this study were to investigate the biochemical steps responsible for enhanced gluconeogenesis as a result of increased dietary fat intake and the site or sites at which the antihyperglycemic agent metformin acts to inhibit this process. Male Hooded Wistar rats were fed either a standard chow diet (5% fat by weight) or a high-fat diet (60% fat by weight) for 14 days with or without metformin. Total endogenous glucose production and gluconeogenesis were determined using [6-3H]glucose and [U-14C]alanine, respectively. Gluconeogenic enzyme activity and, where appropriate, protein and mRNA levels were measured in liver tissues. The high-fat diet increased endogenous glucose production (21.9 ± 4.4 vs. 32.2 ± 4.8 μmol · kg−1 · min−1, P < 0.05) and alanine gluconeogenesis (4.5 ± 0.9 vs. 9.6 ± 1.9 μmol · kg−1 · min−1, P < 0.05). Metformin reduced both endogenous glucose production (32.2 ± 4.8 vs. 16.1 ± 2.1 μmol · kg−1 · min−1, P < 0.05) and alanine gluconeogenesis (9.6 ± 1.9 vs. 4.7 ± 0.8 μmol · kg−1 · min−1, P < 0.05) after high-fat feeding. These changes were reflected in liver fructose-1,6-bisphosphatase protein levels (4.5 ± 0.9 vs. 9.6 ± 1.9 arbitrary units, P < 0.05 chow vs. high-fat feeding; 9.5 ± 1.9 vs. 4.7 ± 0.8 arbitrary units, P < 0.05 high fat fed in the absence vs. presence of metformin) but not in changes to the activity of other gluconeogenic enzymes. There was a significant positive correlation between alanine gluconeogenesis and fructose-1,6-bisphosphatase protein levels ( r = 0.56, P < 0.05). Therefore, excess supply of dietary fat stimulates alanine gluconeogenesis via an increase in fructose-1,6-bisphosphatase protein levels. Metformin predominantly inhibits alanine gluconeogenesis by preventing the fat-induced changes in fructose-1,6-bisphosphatase levels.

scholarly journals Differential and synergistic effects of low birth weight and Western diet on skeletal muscle vasculature, mitochondrial lipid metabolism and insulin signaling in male guinea pigs

2021 ◽  
Author(s):  
Kristyn Dunlop ◽  
Ousseynou Sarr ◽  
Nicole Stachura ◽  
Lin Zhao ◽  
Karen Nygard ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Birth Weight ◽  
Amino Acid ◽  
Low Birth Weight ◽  
Insulin Signaling ◽  
Western Diet ◽  
Whole Body ◽  
High Fat ◽  
Mitochondrial Lipid

Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar Western diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male lean offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism as reflected by in-creased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high fat-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism promoting mitochondrial overload.

scholarly journals Antidiabetic and Antihyperlipidemic Effects ofClitocybe nudaon Glucose Transporter 4 and AMP-Activated Protein Kinase Phosphorylation in High-Fat-Fed Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Mei-Hsing Chen ◽  
Cheng-Hsiu Lin ◽  
Chun-Ching Shih
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transporter ◽  
Body Weight Gain ◽  
Glucose Production ◽  
Hypolipidemic Effect ◽  
Glucose Transporter 4 ◽  
High Fat ◽  
Hepatic Expression ◽  
Amp Activated Protein Kinase

The objective of this study was to evaluate the antihyperlipidemic and antihyperglycemic effects and mechanism of the extract ofClitocybe nuda(CNE), in high-fat- (HF-) fed mice. C57BL/6J was randomly divided into two groups: the control (CON) group was fed with a low-fat diet, whereas the experimental group was fed with a HF diet for 8 weeks. Then, the HF group was subdivided into five groups and was given orally CNE (including C1: 0.2, C2: 0.5, and C3: 1.0 g/kg/day extracts) or rosiglitazone (Rosi) or vehicle for 4 weeks. CNE effectively prevented HF-diet-induced increases in the levels of blood glucose, triglyceride, insulin (P<0.001,P<0.01,P<0.05, resp.) and attenuated insulin resistance. By treatment with CNE, body weight gain, weights of white adipose tissue (WAT) and hepatic triacylglycerol content were reduced; moreover, adipocytes in the visceral depots showed a reduction in size. By treatment with CNE, the protein contents of glucose transporter 4 (GLUT4) were significantly increased in C3-treated group in the skeletal muscle. Furthermore, CNE reduces the hepatic expression of glucose-6-phosphatase (G6Pase) and glucose production. CNE significantly increases protein contents of phospho-AMP-activated protein kinase (AMPK) in the skeletal muscle and adipose and liver tissues. Therefore, it is possible that the activation of AMPK by CNE leads to diminished gluconeogenesis in the liver and enhanced glucose uptake in skeletal muscle. It is shown that CNE exhibits hypolipidemic effect in HF-fed mice by increasing ATGL expression, which is known to help triglyceride to hydrolyze. Moreover, antidiabetic properties of CNE occurred as a result of decreased hepatic glucose production via G6Pase downregulation and improved insulin sensitization. Thus, amelioration of diabetic and dyslipidemic states by CNE in HF-fed mice occurred by regulation of GLUT4, G6Pase, ATGL, and AMPK phosphorylation.

Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes

2005 ◽  
Vol 289 (2) ◽  
pp. E258-E265 ◽  
Author(s):  
Deanna Aftab Guy ◽  
Darleen Sandoval ◽  
M. A. Richardson ◽  
Donna Tate ◽  
Stephen N. Davis
Keyword(s):  
Type 1 Diabetes ◽  
Glycemic Control ◽  
Blood Pressure Response ◽  
Severe Hypoglycemia ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Target Organ ◽  
Epinephrine Infusion ◽  
Glucose Levels

Severe hypoglycemia occurs in intensively treated patients with type 1 diabetes mellitus (T1DM) due in part to deficient epinephrine counterregulatory responses. Previously, we have found that T1DM patients demonstrated a spectrum of altered responses to epinephrine at a variety of target organs compared with nondiabetic healthy subjects. What is not known is whether intensive glycemic control further modifies target organ responses in individuals with T1DM. Therefore, the aim of this study is to assess whether there is tissue specific (liver, muscle, adipose tissue, pancreas and cardiovascular) resistance to epinephrine in intensively controlled (IC) T1DM compared with those with conventional control (CC). Eight IC patients (age 33 ± 4 yr, BMI 24 ± 2 kg/m2, Hb A1C6.7 ± 0.1%), and 11 CC patients (age 35 ± 3 yr, BMI 25 ± 1 kg/m2, Hb A1C9.6 ± 0.1%) underwent two separate randomized, single-blind, 2-h hyperinsulinemic euglycemic clamp studies with (EPI) and without (NO EPI) epinephrine infusion. Epinephrine levels during EPI were similar in all groups (5,197 ± 344 pmol/l). Glucose (5.3 ± 0.1 mmol/l) and insulin levels (515 ± 44 pmol/l) were similar in all groups during the glucose clamps. Endogenous glucose production (EGP) and glucose uptake (Rd) were determined using [3-H3]glucose. Muscle biopsy was performed at the end of each study. IC had a significantly reduced EGP and Rdresponses to EPI compared with CC. Glucagon responses to EPI were similarly blunted in both IC and CC. Free fatty acid and glycerol response to EPI was greater in CC compared with IC. There was a significantly greater systolic blood pressure response to EPI in CC. We conclude that, despite similar epinephrine, insulin, and glucose levels, intensively treated T1DM patients had reduced cardiovascular, skeletal muscle, hepatic, and adipose target organ responses to EPI compared with conventionally treated T1DM patients.

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